Significance. Strabismus - misalignment of the visual axes - affects some 3% of the population and is a significant cause of visual disturbances such as diplopia, amblyopia, and stereoblindness. Definitive therapy for strabismus is usually surgical. Nevertheless, accuracy of surgical treatment remains disappointingly low: 20-50% of cases require multiple surgeries, exposing patients to additional morbidity and expense. A quantitative understanding of the mechanics of extraocular muscles and orbital connective tissues would improve diagnosis and treatment planning, and yet has been elusive. Such an understanding would also facilitate basic research on central or innervational causes of strabismus by allowing mechanical components to be isolated. Aims and Methods. We propose to study the functional anatomy of orbital connective tissues and extraocular muscles in humans and monkeys. We will determine population norms for size and contractility of extraocular muscles in a diverse sample of humans, using magnetic resonance imaging (MRI). Similarly, we will characterize the pathophysiology of selected strabismic patients, focusing on superior oblique and lateral rectus disorders, and the time courses of their resolution. We will characterize orbital connective tissues by dissecting and serially-sectioning human and monkey cadavers, correlating human data with orbital MRI data. In fresh cadavers, we will measure the stiffness of Tenon's fascia and its sleeves, these constituting putative "pulleys" of the rectus muscles. Using histochemical, immunohistochemical, and dye techniques, we will then discover the types and distribution of connective tissues and smooth muscles responsible for mechanical properties measured, as well as smooth muscle innervation. We will image regional stretching of Tenon's fascia as a function of gaze, using radio-opaque markers implanted in trained monkeys. In monkeys we will surgically modify Tenon's sleeves to evaluate mechanical effects and explore avenues for therapeutic enhancement of transposition surgery. We will unify and interpret all findings using the "SQUINT" biomechanical model of binocular alignment, a system of equations describing static equilibrium of the globes and orbital tissues, implemented as a computer program. We will develop and prospectively test SQUINT using extensive pre- and post-operative Hess test binocular alignment data, saccadic measurements, and MRI data, collected specifically for this purpose. We will apply the model to study effects on alignment of post-surgical healing, using it in conjunction with post- surgical data, to infer orbital and innervational changes.